NCCN Clinical Practice Guidelines in Oncology. Melanoma V Continue.

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1 Clinical in Oncology V Continue

2 Panel Members Table of Contents * Daniel G. Coit, MD/Chair Memial Sloan-Kettering Cancer Center Robert Andtbacka, MD Huntsman Cancer Institute at the University of Utah Christopher K. Bichakjian, MD University of Michigan Comprehensive Cancer Center Raza A. Dilawari, MD St. Jude Children s Research Hospital/ University of Tennessee Cancer Institute Dominick DiMaio, MD UNMC Eppley Cancer Center at The Nebraska Medical Center Valerie Guild Consultant Allan C. Halpern, MD Þ Memial Sloan-Kettering Cancer Center F. Stephen Hodi, MD Dana-Farber/Brigham and Women s Cancer Center Mohammed Kashani-Sabet, MD UCSF Helen Diller Family Comprehensive Cancer Center Julie R. Lange, MD, ScM The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Anne Lind, MD Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine Lainie Martin, MD Fox Chase Cancer Center Mary C. Martini, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Scott K. Pruitt, MD, PhD Duke Comprehensive Cancer Center Merrick I. Ross, MD The University of Texas M. D. Anderson Cancer Center Stephen F. Sener, MD Robert H. Lurie Comprehensive Cancer Center of Nthwestern University Jeffrey A. Sosman, MD Vanderbilt-Ingram Cancer Center Susan M. Swetter, MD Stanfd Comprehensive Cancer Center Kenneth K. Tanabe, MD Massachusetts General Hospital Cancer Center * John A. Thompson, MD Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance Vijay Trisal, MD City of Hope Marshall M. Urist, MD University of Alabama at Birmingham Comprehensive Cancer Center Jeffrey Weber, MD, PhD H. Lee Moffitt Cancer Center & Research Institute Michael K. Wong, MD, PhD Roswell Park Cancer Institute Guidelines Panel Disclosures Continue Medical oncology Þ Internal medicine Dermatology Surgery/Surgical oncology Pathology Patient Advocacy Hematology/Hematology oncology * Writing Committee member

3 Table of Contents Table of Contents Panel Members Summary of Guidelines Updates Clinical Presentation and Preliminary Wkup (ME-1) Stage 0 (in situ), Stage I-II (ME-2) Stage III (ME-3) Stage IV (ME-4) Follow-up (ME-5) Persistent disease True local scar recurrence, In-transit recurrence (ME-6) Nodal recurrence (ME-7) Distant metastatic disease (ME-8) Principles of Biopsy (ME-A) Principles of Surgical Margins f Wide Excision of Primary (ME-B) Complete Lymph Node Dissection (ME-C) Principles of Systemic Therapy f Advanced Metastatic (ME-D) Print the Guideline F help using these documents, please click here Staging Discussion References Clinical Trials: The believes that the best management f any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. To find clinical trials online at member institutions, click here: nccn.g/clinical_trials/physician.html Categies of Evidence and Consensus: All recommendations are Categy 2A unless otherwise specified. See Categies of Evidence and Consensus These guidelines are a statement of evidence and consensus of the auths regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care treatment. The National Comprehensive Cancer Netwk makes no representations n warranties of any kind whatsoever regarding their content, use, application and disclaims any responsibility f their application use in any way. These guidelines are copyrighted by National Comprehensive Cancer Netwk. All rights reserved. These guidelines and the illustrations herein may not be reproduced in any fm without the express written permission of

4 Table of Contents Summary of the Guidelines Updates Summary of changes in the version of the guidelines from the version is the addition of the Discussion. Summary of changes in the version of the guidelines from the version include: ( ME-1) Pathology Rept: Mitotic rate moved to third in the list and Clark level was moved to the bottom of the list. Footnote d :...extensive regression and mitotic rate greater than zero was changed to... lymphovascular invasion (LVI) mitotic rate 1 mm 2. ( ME-2) Stage IA with adverse features; Wkup: Further imaging only to evaluate... was changed to Imaging only to evaluate... Footnote h stating Sentinel node biopsy is an imptant staging tool, but the impact of SLNB on overall survival is unclear is new to the page. ( ME-3) Clinical/Pathologic Stage; Stage III pathways: The phrases Nodal micrometastases and Nodal macrometastases were removed. ( ME-5) Clinical/Pathologic Stage: Stage IB-III was changed to Stage IB- IV, NED. Stage I-IV, NED; Follow-up: Chest x-ray, LDH, CBC every 3-12 mo... was changed to...every 6-12 mo... ( ME-6) Persistent disease pathway; Far Right: Recommendations should be stage specific... was changed to Recommendations should be based on stage of recurrence... ( ME-A): Principles of Biopsy Footnote 1 stating If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow margin excision is new to the page. ( ME-B): Principles of Surgical Margins f Wide Excision of Primary Footnote 2 stating Clinical margins may not crelate with histologic margins is new to the page. ( ME-C): Complete Lymph Node Dissection First Bullet: A though dissection... was changed to An anatomically complete dissection... Footnote 1 stating Anatomic boundaries of lymph node dissection should be described in operative rept is new to the page. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. UPDATES

5 Table of Contents CLINICAL PRESENTATION PATHOLOGY REPORT PRELIMINARY WORKUP CLINICAL STAGE Stage 0 in situ Stage IA ( 1 mm thick, Clark level II III) with no adverse featuresd (ME-2) Suspicious pigmented lesion Biopsy a Inadequate b confirmed b Rebiopsy Breslow thickness + Ulceration status + Mitotic rate (categy 2B) + Assess deep and peripheral margin status + Satellitosis, if present, should be repted + Clark level (f lesions 1 mm) H&P with attention to locegional area, draining lymph nodes Complete skin exam Assessment of melanoma related risk facts c Stage IA ( 1 mm thick, Clark level II III) with adverse featuresd (ME-2) Stage IB, Stage II ( 1 mm thick with ulceration Clark level IV, V > 1 mm thick, any characteristic), N0 (ME-2) Stage III (Sentinel node positive) (ME-3) Stage III Clinically positive nodes (ME-3) a See Principles of Biopsy (ME-A). bif diagnostic biopsy is inadequate f treatment decisions, rebiopsy may be appropriate. crisk facts f melanoma include family histy of melanoma, pri primary melanoma, and other facts such as atypical moles/dysplastic nevi. d Adverse features include positive deep margins, lymphovascular invasion (LVI) mitotic rate 1 mm 2. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Stage III in-transit (ME-3) Stage IV Metastatic (ME-4) ME-1

6 CLINICAL STAGE Stage 0 in situ Stage IA 1 mm thick, Clark level II III) with no adverse featuresd Stage IA ( 1 mm thick, Clark level II III) with adverse featuresd Stage IB, Stage II ( 1 mm thick with ulceration Clark level IV, V > 1 mm thick, any characteristic), N0 WORKUP H&P Iimaging only to evaluate specific signs symptoms (CT scan, PET, MRI) H&P (Stage IB, IIA no further wkup required) Chest x-ray (optional); routine imaging not recommended f stage IB, IIA Further imaging as clinically indicated f Stage IIB, IIC patients (CT scan, PET, MRI) Consider sentinel node biopsy f Encourage sentinel node biopsy f,h PRIMARY TREATMENT Wide excision e Wide excisione (categy 1) Wide excisione (categy 1) with sentinel node biopsyg Wide excisione (categy 1) Wide excisione (categy 1) with sentinel node biopsyg dadverse features include positive deep margins, lymphovascular invasion (LVI) mitotic rate 1 mm 2. esee Principles of Surgical Margins f Wide Excision of Primary (ME-B). fdecision to not perfm SLNB may be based on significant patient combidities, patient preference other facts. gsentinel lymph nodes should be evaluated with multiple sectioning and immunohistochemistry. hsentinel node biopsy is an imptant staging tool, but the impact of SLNB on overall survival is unclear. iifn has been associated with improved DFS, however, its impact on overall survival is unclear. Sentinel node negative Sentinel node positive Sentinel node negative Sentinel node positive Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Table of Contents ADJUVANT TREATMENT See Stage III Wkup and Primary Treatment (ME-3) If Stage IB, IIA: Clinical trial Observation If Stage IIB, IIC: Observation Clinical trial Interferon alfai (categy 2B) See Stage III Wkup and Primary Treatment (ME-3) See Follow-Up (ME-5) See Follow-Up (ME-5) ME-2

7 CLINICAL/ PATHOLOGIC STAGE Stage III (Sentinel node positive) WORKUP PRIMARY TREATMENT ADJUVANT TREATMENT Consider baseline imaging f staging and to evaluate specific signs symptoms (categy 2B) (Chest x-ray, CT ± PET, MRI) Lymph node dissection Clinical trialk FNA preferred, if feasible, lymph node biopsy Consider baseline imaging Wide excision of primary tume Stage III f staging and to evaluate (categy 1) (Clinically positive specific signs symptoms + complete lymph node dissectionj node(s)) (categy 2B) Complete surgical excision to clear (Chest x-ray, CT ± PET, MRI) margins, preferred, if feasible Pelvic CT if inguinofemal (categy 2B) nodes positive Consider sentinel node biopsyg (categy 2B) FNA preferred, if feasible, Hyperthermic perfusion/infusion biopsy with melphalan (categy 2B) Consider baseline imaging Stage III Clinical trial f staging and to evaluate in-transit specific signs symptoms Intralesional injection (categy 2B) (BCG, IFN) (categy 2B) (Chest x-ray, CT ± PET, MRI) e Local ablation therapy (categy 2B) See Principles of Surgical Margins f Wide Excision of Primary (ME-B). g RT (categy 2B) Sentinel lymph nodes should be evaluated with multiple sectioning and immunohistochemistry. Systemic therapyl iifn has been associated with improved DFS, however, its impact on overall survival is unclear. j Topical imiquimod (categy 2B) See Complete Lymph Node Dissection (ME-C). kclinical trials assessing alternatives to complete lymph node dissection, such as careful observation. lsee Principles of Systemic Therapy f Advanced Metastatic (ME-D). Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. j Table of Contents Observation Clinical trial Interferon alfa i (categy 2B) Clinical trial Interferon alfa i (categy 2B) Observation and/ Consider RT to nodal basin if Stage IIIC (categy 2B) with multiple nodes involved extranodal extension If free of disease Clinical trial Interferon alfa i (categy 2B) Observation (See Follow-up ME-5) ME-3

8 Table of Contents CLINICAL/ PATHOLOGIC STAGE WORKUP Stage IV Metastatic FNA preferred, if feasible biopsy Chest x-ray and/ chest CT LDH Encourage chest abdominal/pelvic CT, MRI brain, and/ PET as clinically indicated (categy 2B) See Treatment f Limited (Resectable) Disseminated Disease (Unresectable) ME-8) Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-4

9 Table of Contents CLINICAL/ PATHOLOGIC STAGE FOLLOW-UP m RECURRENCE o Stage 0 in situ Stage IA Stage IB-IV NED At least annual skin exam f life Educate patient in monthly self skin exam H&P (with emphasis on nodes and skin) every 3 12 mo f 5 y then annually as clinically indicated At least annual skin exam f life Educate patient in monthly self skin and lymph node exam H&P (with emphasis on nodes and skin) every 3 6 mo f 2 y, then every 3-12 mo f 2 y, then annually as clinically indicated Chest x-ray, LDH, CBC every 6-12 mo (optional) (categy 2B) Routine imaging is not recommended f IB, IIA CT scans to follow-up f specific signs and symptoms. Consider CT scans to screen Stage IIB and higher f recurrent/metastatic disease (categy 2B) At least annual skin exam f life Educate patient in monthly self skin and lymph node exam Persistent disease True local scar recurrence n,o,p Local, satellitosis, and/ in-transit recurrence o,p Nodal recurrence p Distant recurrence p (See ME-6) (See ME-6) (See ME-7) (See ME-8) m n o p Follow-up schedule influenced by risk of recurrence, pri primary melanoma, and family histy of melanoma, and includes other facts, such as atypical moles, dysplastic nevi, and patient anxiety. Persistent disease true local scar recurrence is defined by presence of in situ and/ radial growth phase. Local recurrence without in situ radial growth phase, with deep dermal subcutaneous fat recurrence within the melanoma scar satellite metastasis adjacent to the melanoma scar. Initial clinical recurrence should be confirmed pathologically whenever possible. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-5

10 Table of Contents WORKUP TREATMENT OF RECURRENCE p Persistent disease true local scar recurrence n,o,p Biopsy to confirma,p Wkup appropriate to stage ( See ME-2) Re-excise tum site to appropriate margins. (See ME-B) Consider lymphatic mapping/slnb accding to thickness Recommendations should be based on stage of recurrence; Follow Guidelines as in ( ME-2) Excise lesion(s) to clear margin, preferred, if feasible; consider sentinel node biopsy Hyperthermic perfusion/infusion with melphalan (categy 2B) FNA (preferred) biopsyp Local, satellitosis, Consider baseline imaging Clinical trial and/ f staging and to evaluate in-transit specific signs symptoms Intralesional injection (BCG, IFN) (categy 2B) recurrence o,p (categy 2B) Local ablation therapy (categy 2B) (Chest x-ray, CT ± PET, MRI) RT (categy 2B) Systemic therapyl Topical imiquimod (categy 2B) asee Principles of Biopsy (ME-A). iifn has been associated with improved DFS, however, its impact on overall survival is unclear. lsee Principles of Systemic Therapy f Advanced Metastatic (ME-D). npersistent disease true local scar recurrence is defined by presence of in situ and/ radial growth phase. o Local recurrence without in situ radial growth phase, with deep dermal subcutaneous fat recurrence within the melanoma scar satellite metastasis adjacent to the melanoma scar. pinitial clinical recurrence should be confirmed pathologically by biopsy whenever possible. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. If free of disease Clinical trial, Interferon alfa i (categy 2B) Observation ME-6

11 Table of Contents Nodal recurrence p WORKUP FNA (preferred) lymph node biopsyp Consider baseline imaging f staging and to evaluate specific signs symptoms (categy 2B) (Chest x-ray, CT ± PET, MRI) Pelvic CT if inguinofemal nodes clinically positive No previous dissection Previous dissection Resectable Unresectable Systemic disease TREATMENT OF RECURRENCE p Lymph node dissection j Excise recurrence; if previously incomplete lymph node dissection, complete lymph node dissection Systemic therapyl RT Clinical trial Complete resection Incomplete resection Consider adjuvant RT (categy 2B) and/ Interferon alfa i (categy 2B) Clinical trial Observation Consider adjuvant RT (categy 2B) and/ Interferon alfai (categy 2B) Clinical trial Observation RT and/ Systemic therapy Clinical trial Observation l i j l p IFN has been associated with improved DFS, however, its impact on overall survival is unclear. See Complete Lymph Node Dissection (ME-C). See Principles of Systemic Therapy f Advanced Metastatic (ME-D). Initial clinical recurrence should be confirmed pathologically by biopsy whenever possible. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-7

12 Table of Contents WORKUP TREATMENT OF METASTATIC DISEASE p Limited (Resectable) Resect No evidence of disease Clinical trial Interferon alfa (categy 2B) Observation Distant metastatic disease FNA (preferred) biopsy Chest x-ray and/ chest CT LDH Encourage chest abdominal/pelvic CT ± MRI brain, and/ PET as clinically indicated Observe systemic therapy l, then repeat scans Without brain metastases Negative f other disease Positive f other disease First line therapy l Resect Residual disease If perfmance status 0 2 Karnofsky perfmance sce 60 Treat as disseminated Second line therapy l l p q Disseminated q (Unresectable) With brain metastases (See CNS Cancers Guidelines) See Principles of Systemic Therapy f Advanced Metastatic (ME-D). Initial clinical recurrence should be confirmed pathologically by biopsy whenever possible. In patients with disseminated metastases, resection radiation may be indicated to palliate symptoms such as gastrointestinal bleeding obstruction, ulcerated soft tissue cutaneous metastases, bulky adenopathy. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. Clinical trial (preferred) Systemic therapyl f patients with good perfmance status as clinically indicated Consider palliative resection radiation f symptomatic patientsq Best supptive care ME-8

13 Table of Contents PRINCIPLES OF BIOPSY Excisional biopsy (elliptical, punch, saucerization) with 1-3 mm margins preferred. Avoid wider margins to permit accurate subsequent lymphatic mapping. Full thickness incisional punch biopsy1 of clinically thickest ption of lesion acceptable, in certain anatomic areas (eg, palm/sole, digit, face, ear) f very large lesions. Shave biopsy1,2 may compromise pathologic diagnosis and complete assessment of Breslow thickness, but is acceptable when the index of suspicion is low. Biopsy to be read by a pathologist experienced in pigmented lesions. Minimal elements to be repted should include Breslow thickness (mm), histologic ulceration, Clark level (optional f Breslow > 1 mm), mitotic rate per mm 2, and peripheral and deep margin status of biopsy. Satellitosis, if present, should be repted. Encourage consistent repting of these additional facts (compatible with American Academy of Dermatology recommendations): Location Regression Tum infiltrating lymphocytes (TIL) Vertical growth phase (VGP) Angiolymphatic invasion Neurotropism Histologic subtype 1 If clinical evaluation of incisional biopsy suggests that microstaging is inadequate, consider narrow margin excision. 2 F lentigo maligna, melanoma in situ, a broad shave biopsy may help to optimize diagnostic sampling. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-A

14 Table of Contents PRINCIPLES OF SURGICAL MARGINS FOR WIDE EXCISION OF PRIMARY MELANOMA Tum Thickness In situ mm mm mm > 4 mm Recommended Clinical Margins cm 1.0 cm (categy 1) 1-2 cm (categy 1) 2.0 cm (categy 1) 2.0 cm Margins may be modified to accommodate individual anatomic functional considerations. 1 F large melanoma in situ, lentigo maligna type, surgical margins > 0.5 cm may be necessary to achieve histologically negative margins; techniques f me exhaustive histologic assessment of margins should be considered. 2Clinical margins may not crelate with histologic margins. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-B

15 Table of Contents COMPLETE LYMPH NODE DISSECTION Adequacy of regional lymph node dissection: An anatomically complete dissection1 of involved nodal basin is required. In the groin, consider elective iliac and obturat lymph node dissection if clinically positive superficial nodes 3 superficial nodes positive. (categy 2B) Iliac and obturat lymph node dissection indicated if pelvic CT is positive (categy 2A) if Cloquet s node is positive (categy 2B). 1 Anatomic boundaries of lymph node dissection should be described in operative rept. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-C

16 Table of Contents PRINCIPLES OF SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC MELANOMA First- Second- Line Therapy: Clinical trial (preferred) Dacarbazine (categy 2B) Temozolomide (categy 2B) High-dose Interleukin-2 1 (categy 2B) Dacarbazine- temozolomide-based combination chemotherapy/biochemotherapy, (including cisplatin and vinblastine with without IL-2, interferon alfa) (categy 2B) Paclitaxel (categy 2B) Paclitaxel/cisplatin (categy 2B) Paclitaxel/carboplatin (categy 2B) 1 High-dose Interleukin-2 should not be used f patients with untreated/active brain metastases. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-D (1 of 2)

17 Table of Contents PRINCIPLES OF SYSTEMIC THERAPY FOR ADVANCED OR METASTATIC MELANOMA (REFERENCES) Dacarbazine Serrone L, Zeuli M, Sega FM, et al. Dacarbazine-based chemotherapy f metastatic melanoma: thirty-year experience overview. J Exp Clin Cancer Res 2000;19: Temozolomide Middleton MR, Grob JJ, Aaronson N, et al. Randomized phase III study of temozolomide versus dacarbazine in the treatment of patients with advanced metastatic malignant melanoma. J Clin Oncol 2000;18: High-dose Interleukin-2 Smith FO, Downey SG, Klapper JA, et al. Treatment of metastatic melanoma using interleukin-2 alone in conjunction with vaccines. Clin Cancer Res 2008;14(17): Dacarbazine temozolomide-based combination chemotherapy biochemotherapy including cisplatin, vinblastine, with without interleukin-2 interferon alfa Atkins MB, Hsu J, Lee S, et al. Phase III trial comparing concurrent biochemotherapy with cisplatin, vinblastine, dacarbazine, interleukin-2, and interferon alfa-2b with cisplatin, vinblastine, and dacarbazine alone in patients with metastatic malignant melanoma (E3695): a trial codinated by the eastern cooperative oncology group. J Clin Oncol 2008 Epub Nov 10. Legha SS, Ring S, Eton O, et al. Development of a biochemotherapy regimen with concurrent administration of cisplatin, vinblastine, dacarbazine, interferon alfa, and interleukin-2 f patients with metastatic melanoma. J Clin Oncol 1998;16: Eton O, Legha SS, Bedikian AY, et al. Sequential biochemotherapy versus chemotherapy f metastatic melanoma: results from a phase III randomized trial. J Clin Oncol 2002;20: Paclitaxel Wiernik PH and Einzig AI. Taxol in malignant melanoma. J Natl Cancer Inst Monogr. 15: , Paclitaxel and carboplatin Rao RD, Holtan SG, Ingle JN, et al. Combination of paclitaxel and carboplatin as second-line therapy f patients with metastatic melanoma. Cancer. 2006;106(2): Agarwala SS, Keilholz U, Hogg D, et al. Randomized phase III study of paclitaxel plus carboplatin with without safenib as secondline treatment in patients with advanced melanoma. J Clin Oncol (Meeting Abstracts). 2007;25(18_suppl):8510. Note: All recommendations are categy 2A unless otherwise indicated. Clinical Trials: believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged. ME-D (2 of 2)

18 Table of Contents Staging Table American Joint Committee on Cancer (AJCC) TNM Staging System f Primary Tum (T) TX Primary tum cannot be assessed (e.g., shave biopsy regressed melanoma) T0 Tis T1 No evidence of primary tum in situ 1.0 mm in thickness with without ulceration T1a 1.0 mm in thickness and level II III, no ulceration T1b ulceration 1.0 mm in thickness and level IV V with T mm in thickness with without ulceration T2a T2b mm in thickness, no ulceration mm in thickness, with ulceration T mm in thickness with without ulceration T3a T3b mm in thickness, no ulceration mm in thickness, with ulceration T4 > 4.0 mm in thickness with without ulceration T4a T4b > 4.0 mm in thickness, no ulceration > 4.0 mm in thickness, with ulceration Regional Lymph Nodes (N) NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in one lymph node N1a Clinically occult (microscopic) metastasis N1b Clinically apparent (macroscopic) metastasis N2 Metastasis in two three regional nodes intralymphatic regional metastasis without nodal metastases N2a Clinically occult (microscopic) metastasis N2b Clinically apparent (macroscopic) metastasis N2c Satellite in-transit metastasis without nodal metastasis N3 Metastasis in four me regional lymph nodes, matted metastatic nodes, in-transit metastasis satellite(s) with metastasis in regional node(s) Distant Metastasis (M) MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastases M1a Metastasis to skin, subcutaneous tissue, distant lymph nodes M1b Metastasis to lung M1c Metastasis to all other visceral sites distant metastasis at any site associated with an elevated serum lactic dehydrogenase (LDH) Continue ST-1

19 Table of Contents Staging, continued Clinical Stage Grouping Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIC Stage III Stage IV Histopathologic Type Tis N0 M0 T1a N0 M0 T1b N0 M0 T2a N0 M0 T2b N0 M0 T3a N0 M0 T3b N0 M0 T4a N0 M0 T4b N0 M0 AnyT N1 M0 Any T N2 M0 Any T N3 M0 Any T Any N M1 Note: Clinical staging includes microstaging of the primary melanoma and clinical/radiological evaluations f metastases. By convention, it should be used after complete excision of the primary melanoma with clinical assessment f regional and distant metastases. in situ Malignant melanoma, NOS Superficial spreading melanoma Nodular melanoma Lentigo maligna melanoma Acral lentiginous melanoma Desmoplastic melanoma Epithelioid cell melanoma Spindle cell melanoma Balloon cell melanoma Blue nevus, malignant Malignant melanoma in giant pigmented nevus Pathologic Stage Grouping Stage 0 Stage IA Stage IB Stage IIA Stage IIB Stage IIC Stage IIIA Stage IIIB Stage IIIC Stage IV Tis N0 M0 T1a N0 M0 T1b N0 M0 T2a N0 M0 T2b N0 M0 T3a N0 M0 T3b N0 M0 T4a N0 M0 T4b N0 M0 T1 4a N1a M0 T1 4a N2a M0 T1 4b N1a M0 T1 4b N2a M0 T1 4a N1b M0 T1 4a N2b M0 T1 4a/b N2c M0 T1 4b N1b M0 T1 4b N2b M0 Any T N3 M0 Any T Any N M1 Note: Pathologic staging includes microstaging of the primary melanoma and pathologic infmation about the regional lymph nodes after partial complete lymphadenectomy. Pathologic Stage 0 Stage IA patients are the exception; they do not require pathologic evaluation of their lymph nodes. Used with the permission of the American Joint Committee on Cancer (AJCC), Chicago, Illinois. The iginal and primary source f this infmation is the AJCC Cancer Staging Manual, Sixth Edition (2002) published by Springer- Verlag New Yk. (F me infmation, visit Any citation quotation of this material must be credited to the AJCC as its primary source. The inclusion of this infmation herein does not authize any reuse further distribution without the expressed, written permission of Springer-Verlag New Yk, Inc., on behalf of the AJCC. ST-2

20 Table of Contents Discussion Categies of Evidence and Consensus Categy 1: The recommendation is based on high-level evidence (e.g. randomized controlled trials) and there is unifm consensus. Categy 2A: The recommendation is based on lower-level evidence and there is unifm consensus. Categy 2B: The recommendation is based on lower-level evidence and there is nonunifm consensus (but no maj disagreement). Categy 3: The recommendation is based on any level of evidence but reflects maj disagreement. All recommendations are categy 2A unless otherwise noted. Overview In the year 2008, an estimated 62,480 new cases of melanoma will be diagnosed and about 8,420 patients will die of the disease in the United States. 1 However, these estimates f new cases may represent a substantial underestimation, because many superficial and in-situ melanomas treated in the outpatient setting are not repted. The incidence of melanoma continues to increase dramatically. is increasing in men me rapidly than any other malignancy and, in women me rapidly than any other malignancy except lung cancer. The lifetime risk of developing melanoma in the year 2005 f someone bn in the United States may be as high as one in ranks second to adult leukemia in terms of loss of years of potential life, per death. The median age at diagnosis is 59 years. Risk facts f melanoma include a positive family histy of melanoma, pri melanoma, multiple clinically atypical moles dysplastic nevi, 3,4 and inherited genetic mutations. In addition to genetic facts, sun exposure may also contribute to the development of melanoma. 5 Individuals with an inability to tan and fair skin that sunburns easily have a greater risk of developing melanoma. 6,7 However, melanoma can occur in any ethnic group and also in areas of the body without substantial sun exposure. As with nearly all malignancies, the outcome of melanoma initially depends on the stage at presentation. 8 It is estimated that 82-85% of melanoma patients present with localized disease,10-13% with regional disease, and 2-5% with distant metastatic disease. In general, the prognosis is excellent f patients who present with localized disease and primary tums 1.0 mm less in thickness, with 5-year survival achieved in me than 90% of patients. F patients with localized melanomas me than 1.0 mm in thickness, survival rates range from 50-90%. The likelihood of regional nodal involvement increases with increasing tum thickness. When regional nodes are involved, survival rates are roughly halved. However, within stage III, 5-year survival rates range from 20-70%, depending primarily on the nodal tum burden. Long-term survival in patients with distant metastatic melanoma, taken as a whole, is less than 10%. However, even within stage IV, some patients have a me indolent clinical course that is biologically quite distinct from most patients with advanced disease. By definition, the National Comprehensive Cancer Netwk () practice guidelines cannot incpate all possible clinical variations and are not intended to replace good clinical judgment individualization of treatments. Exceptions to the rule were discussed among the members of the panel during the process of developing these guidelines. A 5% rule (omitting clinical scenarios that comprise less than 5% of all cases) was used to eliminate uncommon clinical MS-1

21 Table of Contents occurrences conditions from these guidelines. The Panel strongly suppts early diagnosis and appropriate treatment of melanoma. Clinical Presentation and Wkup Biopsy Patients presenting with a suspicious pigmented lesion optimally should undergo an excisional biopsy, preferably with 1-3 mm margins (ME-A). The ientation of the excisional biopsy should always be planned with definitive treatment in mind (eg, a longitudinal ientation in the extremities). With the increasing use of lymphatic mapping and sentinel node biopsy, biopsies should also be planned so they will not interfere with this procedure. In this regard, wider margins f the initial diagnostic procedure should be avoided. Excisional biopsy may be inappropriate f certain sites (including the face, palmar surface of the hand, sole of the foot, ear, distal digit, subungual lesions) f very large lesions. In these instances, a full-thickness incisional punch biopsy of the clinically thickest ption of the lesion, rather than a shave biopsy, is an acceptable option. These procedures should provide accurate primary tum microstaging, without interfering with definitive local therapy. If the incisional biopsy is inadequate to make a diagnosis to accurately microstage the tum (based on evaluation by a dermatopathologist) f treatment planning, re-biopsy with narrow margin excision should be considered. Pathology Rept In the revised American Joint Committee of Cancer (AJCC) staging system, melanoma patients are categized into three groups: localized disease with no evidence of metastases (stage I-II), regional disease (stage III) and distant metastatic disease (stage IV). 8,9 Breslow tum thickness and ulceration are the two most imptant characteristics of the primary tum predicting outcome in patients with localized melanoma (stage I II). 10 In the most recent version of the AJCC staging system, Clark level was also a strong independent predict of outcome, f primary melanomas less than 1 mm thick. 8 Mitotic rate (MR) is an indicat of tum proliferation and is measured as the number of mitoses per mm 2. Barnhill et al compared the relative imptance of MR vs. ulceration as maj prognostic facts in localized melanoma. 11 In a multivariate analysis including MR and ulceration, tum thickness, moderate MR (between 1 and 6) and MR greater than 6 emerged as the most imptant independent prognostic fact. Several other studies have also confirmed the prognostic imptance of MR in patients with primary cutaneous melanoma In multivariate analyses MR and younger age were identified as independent predicts of a positive sentinel lymph node (SLN), in addition to Breslow thickness. 15,16 The American Academy of Dermatology (AAD) Task Fce recommends the inclusion of MR in the biopsy rept as optional along with other additional facts such as vertical growth phase (VGP), tum-infiltrating lymphocytes (TIL) and regression. 17 Microscopic satellitosis, if present, should also be recded, as this defines a patient subgroup at high risk f regional and systemic failure, prognostically similar to Stage III. F Stage I-II patients, the melanoma panel recommends the inclusion of Breslow thickness, ulceration status, mitotic rate, deep and peripheral margin status, satellitosis if present and Clark level (especially f lesions 1.0 mm less) in the pathology rept. Mitotic rate should be repted f all lesions, as it is emerging as an independent predict of outcome (categy 2B). The panel agreed that recding of those parameters identified by the AAD task fce would be helpful, but not mandaty. MS-2

22 Table of Contents Among patients with localized melanoma undergoing sentinel lymph node biopsy (SLNB), the status of the sentinel node is the most imptant prognostic fact. 10 Among patients with nodal metastases (stage III), the number of metastatic nodes and clinical nodal status (nonpalpable vs. palpable) are the most imptant predicts of survival, followed by the presence absence of primary tum ulceration. Other prognostically relevant facts include the presence of extranodal tum extension and, in patients with positive sentinel nodes, the size and location of the metastatic melanoma in the sentinel nodes. F Stage III patients, the melanoma panel recommends repting the number of positive nodes, the total number of nodes examined, and the presence absence of extranodal tum extension. In addition, the panel recommends recding the size and location of tum present in a positive sentinel node. The site of metastases is the most significant predict of outcome among patients with distant metastases (Stage IV). Elevated LDH is also an independent predict of po outcome in patients with stage IV disease and has been incpated into the AJCC staging system. 10,18 F Stage IV patients, the melanoma panel recommends repting all sites of metastatic disease, and the serum LDH at diagnosis of Stage IV. Preliminary Wkup After the diagnosis of melanoma has been confirmed, a histy and physical examination (H&P) as well as a complete dermatologic examination are recommended. Preliminary wk up of patient presenting with dysplastic nevi should include detailed personal and family histy including any histy of pri removal of dysplastic nevi. 3 In the physical examination of patients with invasive melanoma, physicians should pay special attention to the locegional area and lymph node drainage of the established melanoma. Clinical Staging Patients can be clinically staged after histopathologic microstaging, an H&P including examination of locegional area and draining lymph nodes, and a complete skin examination (ME-2). In accdance with the AJCC staging system, guidelines have categized patients into the following clinical groups: Stage 0 (melanoma in situ) Stage IA, (1.0 mm less, Clark level II-III) with without potentially adverse features such as positive deep margins, lymphovascular invasion and mitotic rate greater than equal to 1 mm 2 ; Stage IB-II (1.0 mm less with ulceration Clark level IV-V; greater than 1.0 mm, with any characteristic and clinically negative nodes); Stage III, clinically positive nodes Stage III, in-transit disease; Stage IV, distant metastatic disease; Pathologic Staging Patients with clinically localized stage I-II melanoma may be further pathologically staged by lymphatic mapping with sentinel lymph node biopsy. Depending on the primary tum thickness, ulceration, and other facts described above, 5 30% of patients undergoing SLNB will be upstaged from clinical stage I-II to pathologic stage III, based on subclinical micrometastatic disease in the SLN. These patients have a distinctly better prognosis than those patients with clinically positive nodes containing macrometastatic disease. 10,19 The AJCC staging system clearly recognizes this difference in prognosis among patients with pathologic stage III melanoma. 8 MS-3

23 Table of Contents Wkup There are several reasons to embark on an extent of disease wkup in the melanoma patient. One would be to establish a set of baseline images against which to compare future studies in a patient at risk f relapse. Another would be to detect clinically occult disease that would affect immediate treatment decisions. A third reason would be to define homogeneously staged patients f inclusion into clinical trials. Although patients greatly value the negative result of a cross-sectional imaging study, physicians need to be cautious about over interpreting the significance of the findings, recognizing that all tests have relatively insensitive lower limits of resolution. Finally, any test that is dered has with it the very real possibility of detecting findings unrelated to the melanoma, findings that can lead to mbid invasive biopsy procedures, at the very least substantial patient anxiety incurred while awaiting results of interval follow-up studies. The yield of routine blood wk and imaging studies in screening patients with clinical stage I-II melanoma f asymptomatic distant metastatic disease is very low. Screening blood tests are very insensitive, and the findings of cross-sectional imaging are often nonspecific, with frequent false positive findings unrelated to melanoma The yield of imaging studies has been me extensively evaluated in the context of patients with Stage III melanoma. In patients with a positive SLN, the yield of cross-sectional imaging in detecting clinically occult distant metastatic disease ranges from % All series rept a high rate of indeterminate and false positive findings. True positive findings are most often found in patients with ulcerated thick primary tums with large tum burden in their sentinel nodes. In asymptomatic patients with clinically positive nodes, the yield of routine cross sectional imaging is a bit higher than in patients with positive sentinel nodes, repted at 4-16% These series also rept a high incidence of radiologic findings that are unrelated to melanoma. These retrospective studies are repting minimum estimates, as it is very difficult to define a study population of truly imaging-naïve Stage III patients. It is probable that, among the entire denominat of Stage III patients, some would have been defined as stage IV based on imaging befe the study coht was assembled. Furtherme, as the majity of clinical Stage III patients will ultimately develop distant metastases, the inability of computed tomography (CT) scans to detect this at diagnosis of stage III is a relatively po predict of future events. Positron emission tomography (PET) scanning has attracted interest as a means of enhancing detection of subclinical metastatic disease. Most investigats have described very low yield and po sensitivity in detecting metastatic disease in patients with clinically localized melanoma In patients with me advanced stage III disease, PET scan may be me useful. In particular, PET scans can help to characterize lesions found to be indeterminate on CT scan, and often image areas of the body not studied by the routine body CT scans (ie. arms and legs). 32 Recommendations Practices among the member institutions vary greatly with respect to the appropriate wkup of a melanoma patient. In the absence of compelling data beyond the retrospective series cited above, f the most part, the extent of wkup is left to the discretion of the treating physician. Routine imaging studies such as a CT scan, PET scan, magnetic resonance imaging (MRI) are not recommended f patients with localized thin melanomas (stage I). recommendation is consistent with National Institutes of Health (NIH) consensus MS-4

24 Table of Contents guidelines. 33 However, these tests may be perfmed as clinically indicated to evaluate specific signs symptoms in patients with stage II melanoma. A baseline chest x-ray is optional f patients with stage IB-II melanoma, because this test is insensitive f detecting clinically occult distant metastases in the lungs (ME-2). Most panel members acknowledged the low yield of screening CT PET scans in patients with Stage III melanoma. Based on the results of the studies repted in the literature and the absence of conclusive data, the panel left the extent of scanning to the discretion of the treating physician. F patients presenting with clinical stage III disease who have clinically positive node(s), all panel members believe it is appropriate to confirm the suspicion of regional metastatic disease, preferably with fine-needle aspiration (FNA) open biopsy of the clinically enlarged lymph node. Clearly, in patients without an antecedent histy of melanoma, this would have been the initial diagnostic test. A pelvic CT scan is recommended in the setting of inguinofemal lymphadenopathy to rule out associated pelvic retroperitoneal lymphadenopathy. F the small group of patients presenting with stage III in-transit disease, the wkup just outlined f stage III nodal disease, including histologic confirmation of the in-transit metastasis, is appropriate (ME-3). F patients presenting with stage IV distant metastatic disease, all panel members agree it is appropriate to confirm the suspicion of metastatic disease with either FNA (preferred) with open biopsy of the lesion (ME-4). LDH level plus chest x-ray and/ chest CT are recommended. Abdominal/pelvic CT, with without PET, and/ head MRI should be considered (categy 2B). Because patients with metastatic melanoma have a high incidence of brain metastases, brain MRI CT scan with contrast should be perfmed if patients have even minimal suggestions of symptoms physical findings of central nervous system (CNS) involvement, if results of imaging would affect decisions about treatment. Although LDH is not a sensitive marker f detecting metastatic disease, the panel recognizes its prognostic role. It is recommended that serum LDH be obtained at diagnosis of Stage IV disease. Other blood wk may be done at the discretion of the treating physician. Treatment of Primary Wide Excision Surgical excision is the primary treatment f melanoma. Several prospective randomized trials have been conducted in an efft to define optimal surgical margins f primary melanoma. In an international prospective study carried out by the Wld Health Organization (WHO), 612 patients with primary melanomas not thicker than 2.0 mm were randomized to wide excision with one cm three cm margins. 34,35 At a median follow-up of 90 months, local recurrence, disease-free and overall survival rates were similar in both groups. The National Intergroup Trial randomized 468 patients with melanomas that are mm in thickness to wide excision with either two four cm margins. At a median follow-up of ten years, there were no differences in local recurrence, disease-free, overall survival. 36,37 Prospective randomized trials from Sweden have confirmed that satisfacty local control and melanoma specific survival are not compromised by narrower margins. 38,39 In a me recent prospective randomized trial comparing 1 cm vs. 3 cm margins f melanomas thicker than 2 mm, wider margins were associated with a slightly lower rate of combined local/regional/nodal recurrence, but without improvement in local recurrence alone, in melanoma specific survival. 40 A systemic review and meta-analysis also MS-5

25 Table of Contents repted that surgical excision margins no me than 2 cm are adequate and surgical margins should not be less than 1 cm around primary melanoma. 41 Management of lentigo maligna melanoma may present unique problems because of the characteristic, yet unpredictable, subclinical extension of atypical junctional melanocytic hyperplasia which may extend several centimeters beyond the visible margins. Various approaches aimed at complete surgical excision with meticulous margin control, have demonstrated high local control rates and are used at some centers, although they are not universally accepted. 42,43 Recommendations The recommendations f surgical margins f wide excision are based on the results of clinical trials discussed above. In cases where there were no prospective data available (in situ and thick melanoma), recommendations were made based on consensus (ME-B). Note that the clinical/surgical margins discussed here do not necessarily crelate with gross pathological/histological margins. F in-situ melanoma, a measured margin of 0.5 cm around the visible lesion should be obtained. F large in situ lentigo maligna melanoma, surgical margins greater than 0.5 cm may be necessary to achieve histologically negative margins. F patients with stage IA melanoma (1.0 mm less), wide excision with a 1.0 cm margin is recommended (categy 1). Wide excision with a 1-2 cm margin is recommended f patients with melanomas measuring mm in thickness (categy 1). F melanomas measuring me than 2.0 mm in thickness, wide excision with 2.0 cm margins is recommended (categy 1 f tums 4 mm less in thickness; categy 2A f tums me than 4 mm in thickness). Surgical margins may be modified to accommodate individual anatomic cosmetic considerations. The panel recognized that 1-2 cm margins might be acceptable in anatomically difficult areas where a full 2.0 cm margin would be difficult to achieve. Although surgical excision remains the standard of care f in situ melanoma, it is sometimes not feasible due to combidity cosmetically-sensitive tum location. Topical imiquimod has emerged as a treatment option, especially f lentigo maligna However, longterm, comparative studies are still needed and the panel currently did not include specific recommendations f this treatment option f in situ melanoma. Sentinel Lymph Node Biopsy SLNB is a minimally invasive procedure developed to identify patients with nodal metastases and who could be candidates f complete lymph node dissection. 48 MSLT- I, an international multicenter phase III trial, was initiated to evaluate the accuracy, mbidity and use of lymphatic mapping and SLNB f staging patients with early stage melanoma. 49 In a preliminary publication, Mton et al repted an initial sentinel node identification rate of 95%. SLNB was also associated with a low false negative rate and low complication rate. Recently, Mton et al published data from the third interim analysis of results from the MSLT-I trial. 50 In patients with intermediate thickness primary melanoma ( mm), those undergoing wide excision with SLNB (and completion lymph node dissection if their sentinel nodes were positive) had no significant improvement in melanoma-specific survival rates compared to those undergoing initial wide excision and nodal observation and delayed therapeutic lymphadenectomy if necessary. There was an improvement in the estimated 5-year disease-free survival in the SLNB group (78% after SLNB vs. 73% after observation (P= 0.009); this was at least in part due to the higher nodal relapse rate in the observation group. Among patients undergoing SLNB, the sentinel node status was the most imptant prognostic MS-6

26 Table of Contents fact f disease specific survival. Furtherme, among all patients with nodal metastases, those who had immediate lymph node dissection following lymphatic mapping and positive SLNB had higher survival rate than patients who underwent delayed lymphadenectomy f clinical disease (72% vs. 52%). This difference was largely attributed to a lower nodal tum burden in the SLN positive patients than the clinically node positive patients. These results confirm that SLNB is of prognostic value and that the procedure can identify patients with low volume nodal metastases whose survival is superi to that of patients whose nodal metastases are detected on clinical examination. MSLT-II is an ongoing trial in which patients with sentinel node metastases are randomized to undergo either completion lymph node dissection observation. This trial should resolve the issue of whether complete lymph node dissection has an impact on outcome. (clinicaltrials.gov/show/nct ). The value of SLNB f patients with thin melanomas (1.0 mm less) and thick melanomas (4.0 mm greater) was not addressed specifically in the MSLT-I trial. Since patients with thin melanoma have a generally favable prognosis, the role of SLNB in this coht is unclear. Three recent retrospective reviews have shown that, f patients with melanomas less than equal to 1 mm thick, the incidence of positive SLN is 2-5%. 51 Facts predicting an increased probability of a positive SLN in patients with thin melanomas include increasing Breslow thickness and Clark level, higher mitotic rate, and younger age. However, with relatively sht follow-up, only one center has demonstrated any convincing evidence that the SLN status was predictive of outcome in this low risk group of patients. 52 Larger series and longer term follow-up will be required to assess the prognostic value of the SLN in patients with thin melanoma The probability of a positive sentinel node in patients with thick melanoma, 4 mm greater, is 30-40%. Almost every retrospective series has demonstrated that SLN status is a strong independent predict of outcome in patients with thick melanoma Thus, in these high-risk patients, it would seem reasonable to offer SLNB, to help define prognostically homogeneous groups f participation in clinical trials of adjuvant therapy. Recommendations Sentinel node biopsy may be offered to melanoma patients either as standard care in the context of a clinical trial. The melanoma panel does not recommend SLNB f patients with in situ melanoma (stage 0) stage IA melanoma that is 1.0 mm less with no adverse features. Discussion of SLNB should be considered f patients with stage IA thin melanomas (1.0 mm less) with adverse prognostic features such as thickness over 0.75 mm, high mitotic rate, and young patient age. Other facts such as positive deep margins and lymphovascular invasion could be considered indications f SLNB on an individual basis (Categy 2B, ME-2) The significance of tum regression is debatable, with me recent studies repting no association of regression incidence to increased SLN positivity. 63,64 As the yield of a positive sentinel node biopsy in patients with Stage IA melanoma is low and the clinical significance of a positive SLN in these patients remains unclear, any discussion of the procedure in this patient population should reflect those facts. F patients with stage IB stage II melanoma (1.0 mm thick less with ulceration Clark level IV,V if the lesions are me than 1.0 mm thick, the panel encourages the use of SLNB. However, while SLNB is a useful staging tool, its impact on the overall survival of these patients is unclear. In patients who would be candidates f SLNB, the decision to not perfm SLNB may be based on significant patient combidities patient preference. Sentinel nodes should be evaluated with serial sectioning and immunohistochemistry. The validity of sentinel node biopsy in accurately staging patients after pri wide excision is unknown. As MS-7